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Frontiers in Cellular and Infection... 2023Disordered gut microbiota (GM) structure and function may contribute to osteoporosis (OP). This study explores how traditional Chinese medicine (TCM) intervention... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Disordered gut microbiota (GM) structure and function may contribute to osteoporosis (OP). This study explores how traditional Chinese medicine (TCM) intervention affects the structure and function of the GM in patients with OP.
METHOD
In a 3-month clinical study, 43 patients were randomly divided into two groups receiving conventional treatment and combined TCM (Yigu decoction, YGD) treatment. The correlation between the intestinal flora and its metabolites was analyzed using 16S rDNA and untargeted metabolomics and the combination of the two.
RESULTS
After three months of treatment, patients in the treatment group had better bone mineral density (BMD) than those in the control group ( < 0.05). Patients in the treatment group had obvious abundance changes in GM microbes, such as Bacteroides, Escherichia-Shigella, Faecalibacterium, Megamonas, Blautia, Klebsiella, Romboutsia, Akkermansia, and Prevotella_9. The functional changes observed in the GM mainly involved changes in metabolic function, genetic information processing and cellular processes. The metabolites for which major changes were observed were capsazepine, Phe-Tyr, dichlorprop, D-pyroglutamic acid and tamsulosin. These metabolites may act through metabolic pathways, the citrate cycle (TCA cycle) and beta alanine metabolism. Combined analysis showed that the main acting metabolites were dichlorprop, capsazepine, D-pyroglutamic acid and tamsulosin.
CONCLUSION
This study showed that TCM influenced the structure and function of the GM in patients with OP, which may be one mechanism by which TCM promotes the rehabilitation of patients with OP through the GM.
Topics: Humans; Gastrointestinal Microbiome; Pyrrolidonecarboxylic Acid; Tamsulosin; RNA, Ribosomal, 16S
PubMed: 37475958
DOI: 10.3389/fcimb.2023.1091083 -
Clinical Medicine (London, England) Mar 2024This review concerns the rare, acquired, usually iatrogenic, high-anion-gap metabolic acidosis, pyroglutamic acidosis. Pyroglutamate is a derivative of the amino acid... (Review)
Review
This review concerns the rare, acquired, usually iatrogenic, high-anion-gap metabolic acidosis, pyroglutamic acidosis. Pyroglutamate is a derivative of the amino acid glutamate, and is an intermediate in the 'glutathione cycle', by which glutathione is continuously synthesized and broken down. The vast majority of pyroglutamic acidosis cases occur in patients on regular, therapeutic doses of paracetamol. In about a third of cases, flucloxacillin is co-prescribed. In addition, the patients are almost always seriously unwell in other ways, typically with under-nourishment of some form. Paracetamol, with underlying disorders, conspires to divert the glutathione cycle, leading to the overproduction of pyroglutamate. Hypokalaemia is seen in about a third of cases. Once the diagnosis is suspected, it is simple to stop the paracetamol and change the antibiotic (if flucloxacillin is present), pending biochemistry. N-acetyl-cysteine can be given, but while the biochemical justification is compelling, the clinical evidence base is anecdotal.
Topics: Humans; Pyrrolidonecarboxylic Acid; Acetaminophen; Acidosis; Floxacillin; Anti-Bacterial Agents
PubMed: 38431210
DOI: 10.1016/j.clinme.2024.100030 -
Molecules (Basel, Switzerland) Nov 2023Venous thromboembolism is a serious problem because it significantly increases the risk of developing vascular complications in elderly patients with obesity or...
Venous thromboembolism is a serious problem because it significantly increases the risk of developing vascular complications in elderly patients with obesity or immobilization, cancer, and many other diseases. Thus, there is a need to study new therapeutic strategies, including new medicinal agents for the efficient and safe correction of thrombus disorders. In this work, we have synthesized a number of new amides and peptides of 4-amino-5-oxoprolines and studied their antiplatelet and antithrombotic activity in experiments in vitro and in vivo. It has been found that the newly obtained compounds slow down the process of thrombus formation in a model of arterial and venous thrombosis, without affecting plasma hemostasis parameters. (2,4)-4-Amino-1-(4-fluorophenyl)-5-oxoprolyl-()-phenylalanine proved to be the most efficient among the studied derivatives. The results obtained indicate the advisability of further studies on 5-oxoproline derivatives in order to design pharmaceutical agents for the prevention and treatment of the consequences of thrombosis.
Topics: Humans; Aged; Pyrrolidonecarboxylic Acid; Fibrinolytic Agents; Amides; Thrombosis; Peptides; Platelet Aggregation Inhibitors
PubMed: 37959820
DOI: 10.3390/molecules28217401 -
International Journal of Molecular... Jun 2023Post-translationally modified N-terminally truncated amyloid beta peptide with a cyclized form of glutamate at position 3 (pEAβ) is a highly pathogenic molecule with...
Post-translationally modified N-terminally truncated amyloid beta peptide with a cyclized form of glutamate at position 3 (pEAβ) is a highly pathogenic molecule with increased neurotoxicity and propensity for aggregation. In the brains of Alzheimer's Disease (AD) cases, pEAβ represents a major constituent of the amyloid plaque. The data show that pEAβ formation is increased at early pre-symptomatic disease stages, while tau phosphorylation and aggregation mostly occur at later stages of the disease. This suggests that pEAβ accumulation may be an early event in the disease pathogenesis and can be prophylactically targeted to prevent the onset of AD. The vaccine (AV-1986R/A) was generated by chemically conjugating the pEAβ fragment to our universal immunogenic vaccine platform MultiTEP, then formulated in Advax adjuvant. AV-1986R/A showed high immunogenicity and selectivity, with endpoint titers in the range of 10-10 against pEAβ and 10-10 against the full-sized peptide in the 5XFAD AD mouse model. The vaccination showed efficient clearance of the pathology, including non-pyroglutamate-modified plaques, from the mice brains. AV-1986R/A is a novel promising candidate for the immunoprevention of AD. It is the first late preclinical candidate which selectively targets a pathology-specific form of amyloid with minimal immunoreactivity against the full-size peptide. Successful translation into clinic may offer a new avenue for the prevention of AD via vaccination of cognitively unimpaired individuals at risk of disease.
Topics: Mice; Animals; Alzheimer Disease; Amyloid beta-Peptides; Pyrrolidonecarboxylic Acid; Cancer Vaccines; Immunotherapy; Plaque, Amyloid; Brain; Mice, Transgenic; Disease Models, Animal
PubMed: 37372944
DOI: 10.3390/ijms24129797 -
International Journal of Molecular... Apr 2024Diverse chemical and pharmacological strategies are currently being explored to minimize the unwanted side effects of currently used opioid analgesics while achieving...
Diverse chemical and pharmacological strategies are currently being explored to minimize the unwanted side effects of currently used opioid analgesics while achieving effective pain relief. The use of multitarget ligands with activity at more than one receptor represents a promising therapeutic approach. We recently reported a bifunctional peptide-based hybrid LENART01 combining dermorphin and ranatensin pharmacophores, which displays activity to the mu-opioid receptor (MOR) and dopamine D2 receptor (D2R) in rat brains and spinal cords. In this study, we investigated the in vitro binding and functional activities to the human MOR and the in vivo pharmacology of LENART01 in mice after subcutaneous administration. In vitro binding assays showed LENART01 to bind and be selective to the human MOR over the other opioid receptor subtypes and delta, kappa and nociceptin receptors. In the [S]GTPγS binding assay, LENART01 acted as a potent and full agonist to the human MOR. In mice, LENART01 produced dose-dependent antinociceptive effects in formalin-induced inflammatory pain, with increased potency than morphine. Antinociceptive effects were reversed by naloxone, indicating MOR activation in vivo. Behavioral studies also demonstrated LENART01's properties to induce less adverse effects without locomotor dysfunction and withdrawal syndrome compared to conventional opioid analgesics, such as morphine. LENART01 is the first peptide-based MOR-D2R ligand known to date and the first dual MOR-dopamine D2R ligand for which in vivo pharmacology is reported with antinociceptive efficacy and reduced opioid-related side effects. Our current findings may pave the way to new pain therapeutics with limited side effects in acute and chronic use.
Topics: Humans; Rats; Animals; Mice; Analgesics, Opioid; Ligands; Receptors, Opioid; Morphine; Opioid Peptides; Pain; Oligopeptides; Pyrrolidonecarboxylic Acid
PubMed: 38612817
DOI: 10.3390/ijms25074007 -
MBio Oct 2023Exclusively in the Bacteroidetes phylum, most proteins exported across the inner membrane via the Sec system and released into the periplasm by type I signal peptidase...
Exclusively in the Bacteroidetes phylum, most proteins exported across the inner membrane via the Sec system and released into the periplasm by type I signal peptidase have N-terminal glutamine converted to pyroglutamate. The reaction is catalyzed by the periplasmic enzyme glutaminyl cyclase (QC), which is essential for the growth of and other periodontopathogens. Apparently, pyroglutamyl formation stabilizes extracytoplasmic proteins and/or protects them from proteolytic degradation in the periplasm. Given the role of as the keystone pathogen in periodontitis, QC is a promising target for the development of drugs to treat and/or prevent this highly prevalent chronic inflammatory disease leading to tooth loss and associated with severe systemic diseases.
Topics: Humans; Aminoacyltransferases; Periodontitis; Pyrrolidonecarboxylic Acid; Glutamine
PubMed: 37750700
DOI: 10.1128/mbio.00980-23 -
Biochemical and Biophysical Research... Jul 2024Insects have about 50 neuropeptide genes and about 70 genes, coding for neuropeptide G protein-coupled receptors (GPCRs). An important, but small family of...
Insects have about 50 neuropeptide genes and about 70 genes, coding for neuropeptide G protein-coupled receptors (GPCRs). An important, but small family of evolutionarily related insect neuropeptides consists of adipokinetic hormone (AKH), corazonin, and AKH/corazonin-related peptide (ACP). Normally, insects have one specific GPCR for each of these neuropeptides. The tick Ixodes scapularis is not an insect, but belongs to the subphylum Chelicerata, which comprises ticks, scorpions, mites, spiders, and horseshoe crabs. Many of the neuropeptides and neuropeptide GPCRs occurring in insects, also occur in chelicerates, illustrating that insects and chelicerates are evolutionarily closely related. The tick I. scapularis is an ectoparasite and health risk for humans, because it infects its human host with dangerous pathogens during a blood meal. Understanding the biology of ticks will help researchers to prevent tick-borne diseases. By annotating the I. scapularis genome sequence, we previously found that ticks contain as many as five genes, coding for presumed ACP receptors. In the current paper, we cloned these receptors and expressed each of them in Chinese Hamster Ovary (CHO) cells. Each expressed receptor was activated by nanomolar concentrations of ACP, demonstrating that all five receptors were functional ACP receptors. Phylogenetic tree analyses showed that the cloned tick ACP receptors were mostly related to insect ACP receptors and, next, to insect AKH receptors, suggesting that ACP receptor genes and AKH receptor genes originated by gene duplications from a common ancestor. Similar duplications have probably occurred for the ligand genes, during a process of ligand/receptor co-evolution. Interestingly, chelicerates, in contrast to all other arthropods, do not have AKH or AKH receptor genes. Therefore, the ancestor of chelicerates might have lost AKH and AKH receptor genes and functionally replaced them by ACP and ACP receptor genes. For the small family of AKH, ACP, and corazonin receptors and their ligands, gene losses and gene gains occur frequently between the various ecdysozoan clades. Tardigrades, for example, which are well known for their survival in extreme environments, have as many as ten corazonin receptor genes and six corazonin peptide genes, while insects only have one of each, or none.
Topics: Animals; Neuropeptides; Insect Hormones; Ixodes; Receptors, G-Protein-Coupled; Oligopeptides; Pyrrolidonecarboxylic Acid; Phylogeny; Amino Acid Sequence; Cricetulus; CHO Cells; Insect Proteins; Receptors, Neuropeptide
PubMed: 38714013
DOI: 10.1016/j.bbrc.2024.149992 -
Scientific Reports Jul 2023Adipokinetic hormones (AKHs) in Arthopoda are characterized by special sequence features including limited choices of amino acid residues in certain positions, such as...
Adipokinetic hormones (AKHs) in Arthopoda are characterized by special sequence features including limited choices of amino acid residues in certain positions, such as Trp in position 8. Over 100 different AKHs have been described, but de novo sequencing of novel peptide hormones can be a challenge. In a project of analyzing corpora cardiaca extracts from two fly species, two different moths, a termite and a beetle for their AKHs, we noted specific patterns in the fragmentation spectra of octapeptides in electrospray Q-TOF experiments resulting from the presence of Pro in position 6. The preference for cleavage N-terminal to Pro residues created an abundant y″-ion, which, in conjunction with the two b-ions resulting from the fragmentation before and after Pro, provided a marker pattern. As Pro6 occurs in about 61% of known AKHs, this information is highly relevant for sequence elucidation. Moreover, the default presence of Trp8 allowed the use of its immonium ion for AKH candidate identification. In addition, we assembled the known AKH sequences from the literature and sequences of AKH-type format found in the Uniprot database in a single online resource. These efforts assisted in the analysis workflow and led to the assignment of two novel AKHs and evidence for the presence of Melme-CC and Dorpa-AKH in the corpus cardiacum of the scarab beetle Sinodendron cylindricum.
Topics: Animals; Tryptophan; Amino Acid Sequence; Proline; Insect Hormones; Corpora Allata; Moths; Pyrrolidonecarboxylic Acid; Coleoptera
PubMed: 37407598
DOI: 10.1038/s41598-023-38056-2 -
Amino Acids Nov 2023Small neuropeptides from the corpora cardiaca are responsible in cockroaches for the mobilisation of trehalose from the fat body into the haemolymph. Such...
Small neuropeptides from the corpora cardiaca are responsible in cockroaches for the mobilisation of trehalose from the fat body into the haemolymph. Such hypertrehalosaemic hormones (HrTHs) belong to the large family of insect adipokinetic hormones (AKHs); a few HrTHs were previously sequenced from cockroaches, and from genomic and/or transcriptomic information one may predict the genes encoding HrTHs from more species. Definite elucidation of the primary structure of the mature peptide with putative modifications needs analytical chemical methods. In the current study, we use high-resolution mass spectrometry coupled with liquid chromatography to identify unequivocally the HrTHs of 13 cockroach species. Either genomic/transcriptomic information was available for most of the species examined, or from related species. We confirm predicted novel sequences and find hydroxyproline modification for the majority of the peptides. The novel decapeptides are structurally close to Bladi-HrTH, which is found in all seven of the investigated blaberid subfamilies. Bladi-HrTH and all the novel peptides elicit a hypertrehalosaemic response in Periplaneta americana, a blattid cockroach.
Topics: Animals; Cockroaches; Amino Acid Sequence; Oligopeptides; Pyrrolidonecarboxylic Acid; Peptides; Mass Spectrometry; Insect Hormones
PubMed: 37882863
DOI: 10.1007/s00726-023-03337-7 -
Peptides May 2024Thyrotropin-releasing hormone (TRH) acts centrally to exert pleiotropic actions independently from its endocrine function, including antinociceptive effects against...
Thyrotropin-releasing hormone (TRH) acts centrally to exert pleiotropic actions independently from its endocrine function, including antinociceptive effects against somatic pain in rodents. Whether exogenous or endogenous activation of TRH signaling in the brain modulates visceral pain is unknown. Adult male Sprague-Dawley rats received an intracerebroventricular (ICV) injection of the stable TRH analog, RX-77368 (10, 30 and 100 ng/rat) or saline (5 µl) or were semi-restrained and exposed to cold (4°C) for 45 min. The visceromotor response (VMR) to graded phasic colorectal distensions (CRD) was monitored using non-invasive intracolonic pressure manometry. Naloxone (1 mg/kg) was injected subcutaneously 10 min before ICV RX-77368 or saline. Fecal pellet output was monitored for 1 h after ICV injection. RX-77368 ICV (10, 30 and 100 ng/rat) reduced significantly the VMR by 56.7%, 67.1% and 81.1% at 40 mmHg and by 30.3%, 58.9% and 87.4% at 60 mmHg respectively vs ICV saline. Naloxone reduced RX-77368 (30 and 100 ng, ICV) analgesic response by 51% and 28% at 40 mmHg and by 30% and 33% at 60 mmHg respectively, but had no effect per se. The visceral analgesia was mimicked by the acute exposure to cold. At the doses of 30 and 100 ng, ICV RX-77368 induced defecation within 30 min. These data established the antinociceptive action of RX-77368 injected ICV in a model of visceral pain induced by colonic distension through recruitment of both opioid and non-opioid dependent mechanisms.
Topics: Rats; Male; Animals; Rats, Sprague-Dawley; Visceral Pain; Thyrotropin-Releasing Hormone; Analgesics; Naloxone; Colorectal Neoplasms; Pyrrolidonecarboxylic Acid
PubMed: 38423212
DOI: 10.1016/j.peptides.2024.171181